Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions.
FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,509,376, U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,359,003, U.S. Pat. No. 6,509,376, and U.S. Pat. No. 7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. No. 6,509,376, U.S. Pat. No. 7,157,423, and US 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); advanced glycation end products (AGE)-induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034).
The mechanism of action of fumaric acid esters is believed to be mediated by pathways associated with the immunological response. For example, FAEs invoke a shift from a Th1 to Th2 immune response, favorably altering the cytokine profile; inhibit cytokine-induced expression of adhesion molecules such as VCAM-1, ICAM-1 and E-selectin, thereby reducing immune cell extravasation; and deplete lymphocytes through apoptotic mechanisms (Lehmann et al., J Investigative Dermatology 2007, 127, 835-845; Gesser et al., J Investigative Dermatology 2007, 127, 2129-2137; Vandermeeren et al., Biochm Biophys Res Commun 1997, 234, 19-23; and Treumer et al., J Invest Dermatol 2003, 121, 1383-1388).
Recent studies suggest that FAEs are inhibitors of NF-κB activation, a transcription factor that regulates the inducible expression of proinflammatory mediators (D'Acquisto et al., Molecular Interventions 2002, 2(1), 22-35). Accordingly, FAEs have been proposed for use in treating NF-κB mediated diseases (Joshi et al., WO 2002/055066; and Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 7,157,423 and U.S. Pat. No. 6,509,376). Inhibitors of NF-κB activation have also been shown to be useful in angiostatic therapy (Tabruyn and Griffioen, Angiogenesis 2008, 11, 101-106), inflammatory bowel disease (Atreya et al., J Intern Med 2008, 263(6), 591-6); and in animal models of diseases involving inflammation including neutrophilic alveolitis, asthma, hepatitis, inflammatory bowel disease, neurodegeneration, ischemia/reperfusion, septic shock, glomerulonephritis, and rheumatoid arthritis (D'Acquisto et al., Molecular Interventions 2002, 2(1), 22-35).
Studies also suggest that NF-κB inhibition by FAEs may be mediated by interaction with tumor necrosis factor (TNF) signaling. Dimethyl fumarate inhibits TNF-induced tissue factor mRNA and protein expression and TNF-induced DNA binding of NF-κB proteins, and inhibits the TNF-induced nuclear entry of activated NF-κB proteins thereby inhibiting inflammatory gene activation (Loewe et al., J Immunology 2002, 168, 4781-4787). TNF signaling pathways are implicated in the pathogenesis of immune-mediated inflammatory diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis (Tracey et al., Pharmacology & Therapetuics 2008, 117, 244-279).
FUMADERM®, an enteric coated tablet containing a salt mixture of ethyl hydrogen fumarate and dimethyl fumarate (DMF) (2), which is rapidly hydrolyzed to methyl hydrogen fumarate (MHF) (1) in vivo and is regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis.

FUMADERM® is dosed three times/day with 1-2 grams/day administered for the treatment of psoriasis. FUMADERM® exhibits a high degree of interpatient variability with respect to drug absorption and food strongly reduces bioavailability. Absorption is thought to occur in the small intestine with peak levels achieved 5-6 hours after oral administration. Significant side effects occur in 70-90% of patients (Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; and Hoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects of current FAE therapy include gastrointestinal upset including nausea, vomiting, diarrhea, and transient flushing of the skin. Also, DMF exhibits poor aqueous solubility.
Fumaric acid derivatives (Joshi and Strebel, WO 2002/055063, US 2006/0205659, and U.S. Pat. No. 7,157,423 (amide compounds and protein-fumarate conjugates); Joshi et al., WO 2002/055066 and Joshi and Strebel, U.S. Pat. No. 6,355,676 (mono and dialkyl esters); Joshi and Strebel, WO 2003/087174 (carbocyclic and oxacarbocylic compounds); Joshi et al., WO 2006/122652 (thiosuccinates); Joshi et al., US 2008/0233185 (dialkyl and diaryl esters)) and salts (Nilsson et al., US 2008/0004344) have been developed in an effort to overcome the deficiencies of current FAE therapy. Controlled release pharmaceutical compositions comprising fumaric acid esters are disclosed by Nilsson and Müller, WO 2007/042034. Glycolamide ester prodrugs are described by Nielsen and Bundgaard, J Pharm Sci 1988, 77(4), 285-298.
Flachsmann et al., U.S. Pat. No. 7,638,118, discloses compounds having the following chemical formula:
wherein:Z is —OR2 or —Y—(R—NR3R4)n;R can be a linear or branched C2-9 alkyl;R2 can be a linear or branched C1-8 alkyl;R3 and R4, together with the nitrogen atom to which they are bonded, can form an aromatic heterocyclic ring such as a morpholinyl ring; andwhen n is 1, Y can be oxygen.
The compounds are disclosed to be useful for neutralizing odors.
Morpholinoalkyl ester prodrugs of the non-steroidal anti-inflammatory drug niflumic acid exhibit unexpectedly high protection from gastric irritation and ulcerogenicity compared to the parent acid drug (Talath and Gadad, Arzneimittelforschung 2006, 56(11), 744-52). The protective effect is believed to involve absorption of the intact prodrug, which reduces local gastric exposure. Although glycolamide esters of niflumic acid have been synthesized in an effort to improve the biocompatibility of niflumic aid, the effects on gastrointestinal irritation in humans does not appear to have been reported (Talath et al, Arzneimittelforschung 2006, 56(9), 631-9; Gadad et al., Arzneimittelforschung 2002, 52(11), 817-21; Benoit et al., Rev. Odontostomatol Midi Fr. 1975, 4, 249-61; and Los et al., Farmaco Sci. 1981 36(5), 372-85). However, the morpholinoalkyl esters, and specifically the morpholinopropyl and morpholinobutyl esters of niflumic acid were identified as exhibiting the best combination of stability, in vivo anti-inflammatory activity, and low ulcerogenicity in rats (Talath and Gadad, Arzneimittelforschung 2006, 56(11), 744-52).
Gangakhedkar et al., U.S. Patent Publication No. 2010/0048651, discloses compounds having the following chemical formula:
wherein:R1 and R2 are independently chosen from hydrogen, C1-6 alkyl, and substituted C1-6 alkyl;R3 and R4, together with the nitrogen to which they are bonded, can form a C5-10 heteroaryl ring such as a morpholino ring; andR5 can be hydrogen, methyl, ethyl, and C3-6 alkyl;and pharmaceutical compositions containing such compounds for the treatment of diseases including psoriasis, multiple sclerosis, an inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and arthritis. Compounds in which —NR3R4 is a morpholino ring are disclosed in Example 3 (methyl 2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate), Example 28 (methyl 1-methyl-2-morpholin-4-yl-2-oxoethyl(2E)but-2-ene-1,4-dioate), Example 31 ((1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl methyl(2E)but-2-ene-1,4-dioate), and Example 47 ((2E)-3-[(2-morpholin-4-yl-2-oxoethyl)oxycarbonyl]prop-2-enoic acid).